354P Intrinsic dysregulation of the colorectal cancer secretome

Results: GPR65 expression was enriched in PDL1 + tumors within both Javelin101 (p<0.00001) and IMmotion151 (p=0.00006).Non-negative Matrix Factorization clustering in IMmotion151 revealed enrichment of T-effector/proliferative programs in GPR65 high (p<0.00001);this same cluster previously has shown improved ORR and PFS with atezolizumab + bevacizumab versus sunitinib in IMmotion151.Immune deconvolution within IMmotion151 indicated higher immune cell infiltration across B cell, dendritic cell, CD4+ and CD8+ T-cell, and monocytic subsets in GPR65 high tumors (all p<0.00001).Notably, they were also enriched for suppressive populations (regulatory T cells, M2 macrophages; p<0.00001).In RCC explants, PTT-3213 reduced anti-inflammatory cytokines (e.g., IL-10) and increased chemoattractant cytokines (e. g., CCL3), indicating pro-inflammatory, anti-tumor TME with GPR65 inhibition.Conclusions: GPR65 expression marks a highly immune infiltrated yet functionally restrained TME, correlating with PD-L1 expression and T-effector signatures.These findings position GPR65 as a putative therapeutic target and support combination strategies in mRCC, aligning with an ongoing phase 1 trial of a GPR65 inhibitor in solid tumors (NCT06634849).